Metabolic reconstruction reveals ATP salvage as a key response to trimethoprim treatment

Carter, Cailean, Singh, Dipali, Wain, John and Langridge, Gemma C. (2026) Metabolic reconstruction reveals ATP salvage as a key response to trimethoprim treatment. iScience, 29 (4). ISSN 2589-0042

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Abstract

Trimethoprim is a clinically important antibiotic for treating urinary tract infections, yet its mechanism of killing remains elusive due to a cascade of affected metabolic reactions. Metabolites available in growth media can selectively counteract trimethoprim, which affects the interpretation of results. We sought to understand the full scope of trimethoprim's impact on Escherichia coli metabolism and how metabolite availability affects trimethoprim outcomes. We applied flux balance analysis on a genome-scale metabolic model of E. coli to simulate trimethoprim activity under bacteriostatic and bactericidal conditions. Our results suggested that in the absence of environmental purines or nucleosides, trimethoprim induces salvage of ATP to repair DNA. We experimentally validated the result with ATP bioluminescence screening of 96 clinical E. coli isolates. Therefore, the choice of growth media composition significantly changes the outcome of the trimethoprim challenge and opens opportunities for personalized medicine.

Item Type:	Article
Uncontrolled Keywords:	biochemistry,metabolomics,microbiology,general ,/dk/atira/pure/subjectarea/asjc/1000
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:
Related URLs:	https://www.scopus.com/pages/publication...
Depositing User:	LivePure Connector
Date Deposited:	04 Aug 2026 15:21
Last Modified:	04 Aug 2026 15:21
URI:	https://ueaeprints.uea.ac.uk/id/eprint/103982
DOI:	10.1016/j.isci.2026.115377

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